This invention relates to a cardiac pacing system and method for treating patients with congestive heart failure, or patients who are likely to develop congestive heart failure, and in particular as a system and method for periodic high rate cardiac pacing of such patients.
Congestive heart failure (CHF) is an extremely serious affliction. CHF has a great impact on the quality of life; it involves the loss of heart rate variability and rate responsive mechanisms in the heart, leading to impaired ventricular relaxation and low exercise tolerance. The disease afflicts about 4 million Americans in any given year; in the USA alone, there are annually about 400,000 new cases, 1 million hospital admissions, and $8 billion cost of care. While drug treatment improves quality of life, it has little effect on survival. Current pharmacologic treatment includes a combination of diuretics, vasodilators, inotropes, .beta.-blockers, and Angiotensin-Converting-Enzyme (ACE)-inhibitors (Bristow & Gilbert, 1995, "Improvement in Cardiac Myocyte Function by Biological Effects of Medical Therapy: A New Concept in the Treatment of Heart Failure," European Heart Journal 16, Supplement F: 20-31). The effect is a decrease of symptoms, and improved quality of life, but little change in mortality. Moreover, the exercise tolerance of most patients is extremely low, as a consequence of limited oxygen supply through the lungs. Long lasting lack of exercise and malnutrition may contribute to the condition and partly explain the exercise intolerance. Indeed, the lack of exercise and deterioration of cardiac muscle may each contribute to each other, with a snowballing effect (Coats et al., 1992, "Controlled Trial of Physical Training in Chronic Heart Failure: Exercise Performance, Hemodynamics, Ventilation, and Autonomic Function," Circulation 85: 2119-2131).
Heart failure develops generally in the course of months or years, and can be the end stage of chronic hypertension, infarction, angina, or diabetes. Heart failure, however caused, represents an intrinsic property of the muscle, and slow relaxation due to slow intracellular calcium removal by the sarcoplasmic reticulum is an important factor. In the normal, healthy heart the duration of contraction and relaxation decreases with increasing heart rate. This ensures a diastolic period of sufficient duration, which is important (a) for filling of the ventricle, and (b) because coronary perfusion and myocardial oxygen supply occurs only during diastole. The duration of contraction and relaxation is determined by calcium removal from the contractile filaments, mainly by the calcium pump in the sarcoplasmic reticulum. Increased heart rate causes more rapid relaxation due to increased activation of the calcium pump. The latter mechanism is impaired in the hypertrophied or failing heart due to reduced transcription of the genes that supply the calcium pump proteins. Therefore, in heart failure patients an increase of heart rate may almost abolish the diastolic interval, which leads to reduced ventricular filling, and reduces myocardial blood supply (Davies et al., 1995, "Reduced Contraction and Altered Frequency Response of Isolated Ventricular Myocytes From Patients With Heart Failure," Circulation 92: 2540-2549).
In view of the above, the system and method of this invention provide a therapy designed to exercise the heart of a CHF patient in a manner that can be easily tolerated by the patient, and without complications. The basic feature of the therapy provided by the invention is to pace the patient's heart for relatively short periods of the day and at a high rate, eg., 140 beats per minute (bpm) for 20 minutes, once or twice daily. The effect of this pacing regimen is to mimic the effect on the heart of patient training, or exercise. The purpose of the therapy is to provide large variations in heart rate which are designed to enhance the heart's rate responsive mechanisms, eg, rate-dependent activation of the calcium pump. For the patient with CHF, this can be done without the complications which may be associated with normal physical exercise.
The therapy provided by the system and method of this invention is applicable either to patients who already have CHF, or to patients who are indicated as likely near term candidates for developing CHF. For patients with CHF, the system provides therapy which exercises the heart without the complications associated with normal physical exercise. For patients who do not have CHF but who are in danger of CHF, the system provides for automatically scheduled or patient-enabled high rate pacing of a form and duration adapted to a patient's tolerance of exercise, so that the patient can establish an exercise regimen which will improve heart function, peripheral circulation, skeletal muscle properties and neurohormonal function.
The premise of the therapy provided by this invention is that the rate responsive mechanisms in the heart muscle are enhanced by pacing with episodes of high rates. It is known that in general physiologic mechanisms tend to adapt to changing demands and that, in particular, muscle fibers can be transformed by proper stimulation protocols. In normal subjects, heart rate varies continuously throughout the day, related to the circadian rhythm, breathing, and blood pressure regulation; transients of high rate occur particularly during physical exercise. The variations in heart rate, however, are relatively small in patients with myocardial infarction, coronary artery disease, and in patients with hypertrophy or heart failure. On the other hand, the literature discloses that ventricular relaxation in old rats is much slower than in young rats; but that exercise training led to faster relaxation in the old rats (Gwathmey et al, 1990, J. Appl Phsiol 69: 1366-1371). The enhanced relaxation may be a long-term adaptation to the transient heart rate increases during exercise. Insulin is an important hormone in the regulation of normal cell growth and differentiation. There are indications that in animals with myocardial hypertrophy insulin may prevent or delay the transition to heart failure. (Rupp et al, 1988, Biochem Biophys Res Comm 156:917-923). It has been suggested that exercise may increase the insulin sensitivity in the heart. (Roubenoff and Rall, 1993). Therefore, periodic high rate pacing may increase the insulin sensitivity in the heart.
It is to be noted that there are potential adverse effects to high rate pacing, which the system and method of this invention must take into account. In the chronic ischemic heart, high rate pacing may lead to increased diastolic pressure, indicating calcium overload and damage of the muscle fibers. For this reason, the disclosed therapy may not be applicable to such patients. For a patient with CHF where the therapy is applied without exercise and concomitant activation of skeletal muscles, the result is an increase in oxygen consumption in the heart only, i.e., general hypoxia in the body will not occur. In failing hearts with relatively normal coronary arteries end-diastolic volume and pressure decrease with increasing heart rate; this may improve cardiac blood supply. However, in patients with advanced CHF, the endocardial coronary reserve is often exhausted. Therefore, the therapy provided by this invention may not apply to patients with end-stage failure, and in any event the maximum pacing rate applied must be adjusted for each patient so as to maintain it below the rate at which myocardial hypoxia develops.